Chronic fatigue syndrome (CFS) is an illness characterized by disabling fatigue, and fibromyalgia (FM) an illness characterized by body-wide pain. These two medically unexplained illnesses often exist together. An unanswered question asked in the research and clinical communities involved with these is: Are they a spectrum of the same condition with the same underlying mechanisms? Knowing that answer could influence treatment using existing medications and modalities. Different pathophysiological processes will mean different paths to treatment. Knowing the list of associated proteins in the central nervous system, i.e. the proteome of one or both would be an invaluable resource and help researcher explore new avenues for therapy. Our proposal will unequivocally deliver the next generation proteome for CFS. The same approach will produce data that lays the foundation to determine if the illnesses the same, variants, or different. We will use high resolution mass spectrometry and protein separation methods that are not biased to determine the proteins in the cerebrospinal fluid of each group. We focus on cerebrospinal fluid, the liquid window to the brain, the organ most likely responsible for the symptoms. We approached a similar question of ?same or different? by comparing the cerebrospinal fluid proteome of CFS to that of another fatigue syndrome ?post treatment Lyme disease patients and controls. We found that the proteome of CFS patients had over 700 proteins which differentiated it from the Lyme patients and controls. Thus there is little doubt that on a technical level we can deliver the proteomes to help answer the above question. If the pathophysiological process producing each illness is the same, then the proteomes of each should closely resemble one another. But if the diseases have a different underlying cause, then the proteomes of each should be markedly different. This R21 proposal has a single Specific Aim: To determine if CFS is distinct from FM by generating and comparing the Proteomes of CFS alone to that of CFS+FM We are fortunate because we have banked cerebrospinal fluid and metadata from patients meeting either the CDC criteria for CFS or American College of Rheumatology criterial for FM. !